Impaired Sprouting and Axonal Atrophy in Cerebellar Climbing Fibres following In Vivo Silencing of the Growth-Associated Protein GAP-43

The adult mammalian central nervous system has a limited ability to establish new connections and to recover from traumatic or degenerative events. The olivo-cerebellar network represents an excellent model to investigate neuroprotection and repair in the brain during adulthood, due to its high plasticity and ordered synaptic organization. To shed light on the molecular mechanisms involved in these events, we focused on the growth-associated protein GAP-43 (also known as B-50 or neuromodulin). During development, this protein plays a crucial role in growth and in branch formation of neurites, while in the adult it is only expressed in a few brain regions, including the inferior olive (IO) where climbing fibres (CFs) originate. Following axotomy GAP-43 is usually up-regulated in association with regeneration. Here we describe an in vivo lentiviral-mediated gene silencing approach, used for the first time in the olivo-cerebellar system, to efficiently and specifically downregulate GAP-43 in rodents CFs. We show that lack of GAP-43 causes an atrophy of the CF in non-traumatic conditions, consisting in a decrease of its length, branching and number of synaptic boutons. We also investigated CF regenerative ability by inducing a subtotal lesion of the IO. Noteworthy, surviving CFs lacking GAP-43 were largely unable to sprout on surrounding Purkinje cells. Collectively, our results demonstrate that GAP-43 is essential both to maintain CFs structure in non-traumatic condition and to promote sprouting after partial lesion of the IO

Improved structure and function in early detected second eye neovascular age-related macular degeneration; FASBAT/EDNA report 1

PURPOSE: Visual Acuity (VA) and structural biomarker assessment before and at 24-months after early detection and routine treatment of second eye involvement with neovascular age-related macular degeneration (nAMD) and additional comparison with the first eye affected. DESIGN: Prospective, 22-centre observational study of participants with unilateral nAMD in the Early Detection of Neovascular AMD (EDNA) study, co-enrolled into the Observing fibrosis, macular atrophy and subretinal highly reflective material, before and after intervention with anti-VEGF treatment (FASBAT) study for an additional 2-year follow-up. PARTICIPANTS: Older adults (>50 years) with new onset nAMD in the first eye. METHODS: Assessment of both eyes with optical coherence tomography (OCT), colour fundus photography (CFP), clinic-measured visual acuity (VA) and quality-of-life (QoL). MAIN OUTCOME MEASURES: Prevalence of Atrophy, Subretinal Hyperreflective Material (SHRM), Intraretinal fluid (IRF), Subretinal fluid (SRF) and changes in VA over the study duration in both the first and second eyes affected with nAMD. Composite QoL scores over time. RESULTS: Of 431 participants recruited to the FASBAT study, the second eye converted to nAMD in 100 participants at a mean of 18.9 months. VA was 18 letters better at the time of early diagnosis in the second eye compared with conventional diagnosis in the first eye (72.9 vs 55.6 letters). 24.9-months post-conversion in the second eye, VA was 69.5 letters compared with at a similar matched time point in the first eye (59.7 letters; 18.9 months). A greater proportion of participants had vision >70 letters in the second eye versus the first eye, 24.9-months post-conversion (61 vs 38). Prevalence of SHRM and IRF was lower in the second eye compared with the first eye at 24.9-months post-conversion to nAMD. However, SRF prevalence was greater in the second eye at 24.9-months post-conversion. The development and progression of total area of atrophy appears similar in both eyes. Mean composite QoL scores increased over time, with a significant correlation between VA for the second eye only 24.9 months post-conversion. CONCLUSION: This study has shown that early detection of exudative AMD in the second eye is associated with reduced prevalence of SHRM and IRF and greater visual acuity which is significantly correlated with maintained quality-of-life

Mechanisms of leukocyte migration across the blood–retina barrier

Immune-mediated inflammation in the retina is regulated by a combination of anatomical, physiological and immuno-regulatory mechanisms, referred to as the blood–retina barrier (BRB). The BRB is thought to be part of the specialised ocular microenvironment that confers protection or “immune privilege” by deviating or suppressing destructive inflammation. The barrier between the blood circulation and the retina is maintained at two separate anatomical sites. These are the endothelial cells of the inner retinal vasculature and the retinal pigment epithelial cells on Bruch’s membrane between the fenestrated choroidal vessels and the outer retina. The structure and regulation of the tight junctions forming the physical barrier are described. For leukocyte migration across the BRB to occur, changes are needed in both the leukocytes themselves and the cells forming the barrier. We review how the blood–retina barrier is compromised in various inflammatory diseases and discuss the mechanisms controlling leukocyte subset migration into the retina in uveoretinitis in more detail. In particular, we examine the relative roles of selectins and integrins in leukocyte interactions with the vascular endothelium and the pivotal role of chemokines in selective recruitment of leukocyte subsets, triggering adhesion, diapedesis and migration of inflammatory cells into the retinal tissue

Seizure prediction : ready for a new era

Acknowledgements: The authors acknowledge colleagues in the international seizure prediction group for valuable discussions. L.K. acknowledges funding support from the National Health and Medical Research Council (APP1130468) and the James S. McDonnell Foundation (220020419) and acknowledges the contribution of Dean R. Freestone at the University of Melbourne, Australia, to the creation of Fig. 3.Peer reviewedPostprin

An overview of geospatial methods used in unintentional injury epidemiology

BACKGROUND: Injuries are a leading cause of death and disability around the world. Injury incidence is often associated with socio-economic and physical environmental factors. The application of geospatial methods has been recognised as important to gain greater understanding of the complex nature of injury and the associated diverse range of geographically-diverse risk factors. Therefore, the aim of this paper is to provide an overview of geospatial methods applied in unintentional injury epidemiological studies. METHODS: Nine electronic databases were searched for papers published in 2000-2015, inclusive. Included were papers reporting unintentional injuries using geospatial methods for one or more categories of spatial epidemiological methods (mapping; clustering/cluster detection; and ecological analysis). Results describe the included injury cause categories, types of data and details relating to the applied geospatial methods. RESULTS: From over 6,000 articles, 67 studies met all inclusion criteria. The major categories of injury data reported with geospatial methods were road traffic (n = 36), falls (n = 11), burns (n = 9), drowning (n = 4), and others (n = 7). Grouped by categories, mapping was the most frequently used method, with 62 (93%) studies applying this approach independently or in conjunction with other geospatial methods. Clustering/cluster detection methods were less common, applied in 27 (40%) studies. Three studies (4%) applied spatial regression methods (one study using a conditional autoregressive model and two studies using geographically weighted regression) to examine the relationship between injury incidence (drowning, road deaths) with aggregated data in relation to explanatory factors (socio-economic and environmental). CONCLUSION: The number of studies using geospatial methods to investigate unintentional injuries has increased over recent years. While the majority of studies have focused on road traffic injuries, other injury cause categories, particularly falls and burns, have also demonstrated the application of these methods. Geospatial investigations of injury have largely been limited to mapping of data to visualise spatial structures. Use of more sophisticated approaches will help to understand a broader range of spatial risk factors, which remain under-explored when using traditional epidemiological approaches

At last, a predictive and prognostic marker for radiotherapy?

Holliday junction recognition protein (HJURP) levels in breast cancer associate with both poor prognosis and an increased sensitivity to irradiation. Whilst, in part, this could be explained in relation to proliferation, it would not entirely account for the association with sensitivity to radiation. Thus, HJURP may have clinical potential as a marker of prognosis and radiation sensitivity; further validation with tissues from randomised controlled trials is needed. HJURP may represent the first in a class of proteins with roles in chromosome segregation and DNA repair that act as predictive biomarkers